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Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated

Robert K Nuttall¹, Claudia Silva, Walter Hader

¹School of Biological Sciences, University of East Anglia, Norwich, United Kingdom.

|January 12, 2007

Abstract:

Microglia are resident immune cells within the central nervous system (CNS). They become activated following neurological insults and increase their expression of cytokines. Also elevated in CNS injuries are proteases, including matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). The spectrum of metalloproteinase members expressed by microglia and by the systemic leukocytes that infiltrate the injured CNS is unknown, as are their functions. We determined the levels of transcripts encoding all 24 MMPs, nine ADAMs, and their four physiological antagonists, tissue inhibitor of metalloproteinases (TIMPs), in human microglia, B and T cells, monocytes, and neutrophils. We found a distinct pattern for each immune subset and an enrichment of metalloproteinases in microglia compared with leukocytes. When microglia were activated, there was an upregulation of transcripts for nine metalloproteinases, and reduction of TIMP3. Activation of microglia also resulted in increased levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 protein in the conditioned media of cells. The amount of secreted TNF-alpha, but not IL-1beta or IL-10, was suppressed by BB94, a broad spectrum metalloproteinase inhibitor, and by TIMP3 but not TIMP1 or TIMP2. This inhibitory profile suggests the involvement of an ADAM member in TNF-alpha secretion. We conclude that microglia bear a metalloproteinase signature distinct from systemic cells, and that following activation, microglia upregulate TNF-alpha protein levels through a combination of elevated cytokine transcripts, increased metalloproteinase level and activity, and through the decrease of TIMP3. The results have implications for the regulation of neuroinflammation and its outcomes following CNS injuries.

Insights

Microglia, the brain's immune cells, express unique metalloproteinases (MMPs and ADAMs) compared to other immune cells. Activated microglia increase specific MMPs and decrease TIMP3, contributing to neuroinflammation and TNF-alpha secretion.

Area of Science:

Neuroimmunology
Protease biology

Background:

Microglia are key immune cells in the central nervous system (CNS).
Neurological injuries activate microglia, increasing cytokine and protease expression.
The specific metalloproteinases (MMPs, ADAMs) and their inhibitors (TIMPs) in microglia and infiltrating leukocytes are not fully characterized.

Purpose of the Study:

To determine the expression profile of all known metalloproteinases and their inhibitors in human microglia and various systemic immune cells.
To investigate how microglial activation affects the expression of these proteases and their inhibitors.
To elucidate the role of metalloproteinases in the secretion of inflammatory cytokines, particularly TNF-alpha, by activated microglia.

Main Methods:

Quantitative analysis of transcripts for 24 MMPs, 9 ADAMs, and 4 TIMPs in isolated human microglia, B cells, T cells, monocytes, and neutrophils.
Assessment of microglial activation markers, including cytokine protein levels (TNF-alpha, IL-1beta, IL-10) in cell culture.
Inhibition studies using a metalloproteinase inhibitor (BB94) and specific TIMPs to assess their effect on cytokine secretion.

Main Results:

Microglia exhibit a distinct metalloproteinase expression pattern compared to peripheral leukocytes, with higher overall metalloproteinase enrichment.
Microglial activation led to upregulation of transcripts for nine metalloproteinases and downregulation of TIMP3.
Activated microglia secreted increased levels of TNF-alpha, IL-1beta, and IL-10; TNF-alpha secretion was partially inhibited by a metalloproteinase inhibitor and TIMP3, suggesting involvement of an ADAM member.

Conclusions:

Microglia possess a unique metalloproteinase signature distinct from systemic immune cells.
Activated microglia enhance TNF-alpha secretion via increased cytokine transcripts, elevated metalloproteinase activity, and reduced TIMP3 levels.
These findings offer insights into the regulation of neuroinflammation and its consequences in CNS injuries.

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